While three Big Pharma companies have yet to successfully crack the ROS1 lung cancer market, young biotech Nuvalent believes competitive pivotal data from its investigational drug are paving the way to a quick FDA filing and, eventually, a chance at a major opportunity.
The eight-year-old Massachusetts biotech’s novel tyrosine kinase inhibitor (TKI) zidesamtinib mounted a 44% overall response rate in a group of 117 patients with heavily pretreated advanced ROS1-positive non-small cell lung cancer (NSCLC), according to the primary analysis of the phase 1/2 Arros-1 trial.
The ORR number looked competitive compared with existing ROS1 inhibitor options from Bristol Myers Squibb and newly approved Nuvation Bio, especially considering half of the patients in the Nuvalent study had received two or more prior ROS1 TKIs, with or without chemotherapy.
Of those half patients, 93% had received newer TKIs, namely Pfizer’s Lorbrena, BMS’ Augtyro and Nuvation’s Ibtrozi. Not approved specifically in ROS1 NSCLC, Lorbrena is Pfizer’s more potent follow-up to its old TKI Xalkori, which does not penetrate the blood-brain barrier. Augtyro was only approved last year and Ibtrozi earlier this month.
“There is no other study that looks at such an advanced, difficult-to-treat patient population that we’re aware of,” Nuvalent CEO Jim Porter, Ph.D., said in an interview with Fierce Biotech. “These patients have already taken these other brain-penetrant TKIs, and the drug is still active in that setting.”
Competitive efficacy data
For reference, Augtyro showed a 38% ORR in 56 patients who had received one prior ROS1 TKI (mostly Xalkori) in the Trident-1 trial. Ibtrozi recorded ORR of 52% and 62% in two separate single-arm trials in patients who had failed on one ROS1 TKI, which was either exclusively or predominantly Xalkori.
Among patients who had tried one prior TKI—with about a 50-50 split between old Xalkori and Roche’s second-generation Rozlytrek—zidesamtinib logged a 51% ORR. Zeroing in further on a subgroup of patients who had previously got Xalkori as their only prior TKI, the ORR became 68%.
Brain metastases are common in ROS1-positive NSCLC, particularly after disease progression. Among 56 patients with measurable brain lesions, zidesamtinib mounted a 48% intracranial ORR, including 20% intracranial complete responses.
If ORR numbers were hard to compare side by side, zidesamtinib’s duration of response clearly stood out from the crowd. While the median duration of response (mDOR) continues to mature in Arros-1, an impressive 93% of zidesamtinib takers who had got just one prior TKI remained in remission after at least 18 months.
In the entire primary analysis cohort, the 12-month DOR rate was 78%, and the 18-month rate was 62%. The primary analysis has DOR follow-up of at least six months for nearly all responders.
By comparison, the 12-month DOR rate was 48% for Augtyro and about 45% for Ibtrozi in their separate studies in TKI-pretreated patients, according to the drugs’ FDA labels.
As patients may stay longer on zidesamtinib compared with other TKIs, Jefferies analyst Roger Song, M.D., sees greater commercial opportunity for the Nuvalent med. The analyst projected about $1.3 billion in adjusted peak sales for zidesamtinib in a Tuesday note.
Porter attributed zidesamtinib’s long DOR to the ability to continuously treat patients at the desirable dose thanks to the drug’s selective targeting of ROS1 while avoiding inhibition of the structurally related TRK protein family.
“The challenge we heard from physicians was keeping patients on therapeutically relevant dose levels,” Porter explained.
Selective targeting of ROS1
While the dual targeting of TRK allows other existing ROS1 inhibitors to treat tumors with NTRK gene fusions, it led to some unwanted neurotoxicities in ROS1 NSCLC. The result is dose reductions or interruptions and hence ineffective suppression of ROS1, Porter said.
Experts have indicated that the tolerability profile of Augtyro and Rozlytrek has limited the length of time patients are able to stay on the drug, Leerink Partners analysts observed in a June 10 note. Although these newer agents are available, Xalkori has maintained the majority of the ROS1 market share despite its lack of activity at key mutations, the analysts noted.
Despite their additional uses in NTRK solid tumors, Augtyro and Rozlytrek together only ginned up about $200 million in sales in 2024.
With zidesamtinib, Nuvalent didn’t see those TRK-related neurotoxicity signals, Porter said. The most frequent treatment-emergent adverse events (TEAEs) that occurred in at least 15% of patients were peripheral edema (36%), constipation (17%), blood CPK increase (16%), fatigue (16%) and dyspnea (15%).
Among 432 patients who received zidesamtinib at the recommended phase 2 dose, dose reductions due to TEAEs happened in 10% of patients, and 2% of individuals discontinued treatment due to TEAEs.
Among existing TKIs, Ibtrozi was also designed with more affinity with ROS1 than TRK. Thanks to that, the Nuvation drug’s FDA label does not include any warnings for central nervous system–related adverse events, giving it an advantage over BMS’ Augtyro. Still, Ibtrozi has been linked to 22% dizziness, including 0.3% grade 3 or 4.
Ibtrozi’s label does include warnings for liver toxicity and QTc interval prolongation, a potentially life-threatening cardiac side effect. A small number of death cases around hepatotoxicity and cardiac events have occurred in patients who got Ibtrozi.
Porter declined to offer additional information on zidesamtinib’s safety profile beyond a Tuesday press release.
Regulatory and business plans
With the latest data, the FDA and Nuvalent have agreed on a plan for a new drug application under the agency’s real-time oncology review program, which allows for early submission before the full package is ready. The company plans to start a rolling submission in July for zidesamtinib for TKI-pretreated NSCLC, with the goal of wrapping up the filing in the third quarter.
As to whether there will be another data cut in the future before an FDA decision, Porter said Nuvalent believes the company has all the necessary data. But, citing past examples in the ROS1 space, he noted that the FDA might want to look at an updated durability cut. Arros-1 has been significantly overenrolled, giving the company the opportunity to have a lot more data in the future, he said.
Together with the primary analysis in the TKI-pretreated population, Nuvalent on Tuesday also offered the first glimpse into data from the phase 2 TKI-naïve cohort of the Arros-1 study.
Among 35 TKI-naïve patients, zidesamtinib at the recommended phase 2 dose showed a preliminary ORR of 89% and a 96% 12-month DOR. As of June 16, the TKI-naïve cohort had enrolled altogether 104 patients.
Nuvalent has not guided to a filing timeline for a TKI-naïve indication, although Porter noted that precedent has been set for following those patients for at least a year post response.
“We’ll continue to work with the regulators to get the drug approved for all ROS1 patients,” he said.
Both Roche and BMS got their ROS1 drugs from acquisitions—Roche from its $1.7 billion purchase of Ignyta and BMS a $4.1 billion takeover of Turning Point Therapeutics.
Being bought out by a large pharma company is not the strategy that Nuvalent has designed for the business, and the biotech has been building its in-house commercial team in the past year or so, Porter said.
“We don’t sit around thinking about who’s going to come acquire us,” the CEO said. “That’s not the goal.”
But the company is looking for commercial partners outside the U.S., Porter said, and, “now, it’s time to find that right global partner.”
Editor's Note: The story was updated with additional comments from a Jefferies note.